The invention relates to indeno[1,2-c]isoquinoline compounds; compositions comprising an indeno[1,2-c]isoquinoline compound; and methods for treating or preventing an inflammatory disease or a reperfusion disease.
Inflammatory diseases, such as arthritis, colitis, and autoimmune diabetes, typically manifest themselves as disorders distinct from those associated with reperfusion diseases, e.g., stroke and heart attack, and can clinically manifest themselves as different entities. However, there can be common underlying mechanisms between these two types of disorders. In particular, inflammatory disease and reperfusion disease can induce proinflammatory cytokine and chemokine synthesis which can, in turn, result in production of cytotoxic free radicals such as nitric oxide and superoxide. NO and superoxide can react to form peroxynitrite (ONOOxe2x88x92) (Szabxc3x3 et al., Shock 6:79-88, 1996).
The ONOOxe2x88x92-induced cell necrosis observed in inflammatory disease and in reperfusion disease involves the activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS). Activation of PARS is thought to be an important step in the cell-mediated death observed in inflammation and reperfusion disease (Szabxc3x3 et al., Trends Pharmacol. Sci. 19: 287-98, 1998).
A number of PARS inhibitors have been described in the art. See, e.g., Banasik et al., J. Biol. Chem., 267:1569-75, 1992, and Banasik et al., Mol. Cell. Biochem., 138:185-97, 1994; WO 00/39104; WO 00/39070; WO 99/59975; WO 99/59973; WO 99/11649; WO 99/11645; WO 99/11644; WO 99/11628; WO 99/11623; WO 99/11311; WO 00/42040; Zhang et al., Biochem. Biophys. Res. Commun., 278:590-98,2000; White et al., J. Med. Chem., 43 :4084-4097, 2000; Griffin et al., J. Med. Chem., 41:5247-5256, 1998; Shinkwin et al., Bioorg. Med. Chem., 7:297-308, 1999; and Soriano et al., Nature Medicine, 7:108-113, 2001. Adverse effects associated with administration of PARS inhibitors have been discussed in Milan et al, Science, 223:589-591, 1984.
Indeno[1,2-c]isoquinoline derivatives have been previously discussed in the art. For example, cytotoxic non-camptothecin topoisomerase I inhibitors are reported in Cushman et al., J. Med. Chem., 43:3688-3698, 2000 and Cushman et al., J. Med. Chem. 42:446-57, 1999; indeno[1,2-c]isoquinolines are reported as antineoplastic agents in Cushman et al., WO 00/21537; and as neoplasm inhibitors in Hrbata et al., WO 93/05023.
Syntheses of indeno[1,2-c]isoquinoline derivatives have been reported. For example, see Wawzonek et al., Org. Prep. Proc. Int. 14:163-8, 1982; Wawzonek et al., Can. J. Chem. 59:2833, 1981; Andoi et al, Bull. Chem. Soc. Japan, 47:1014-17, 1974; Dusemund et al., Arch. Pharm (Weinheim, Ger.), 3 17:381-2, 1984; and Lal et al., Indian J. Chem., Sect. B, 38B:33-39, 1999.
There remains, however, a need in the art for compounds useful for treating or preventing inflammatory diseases or reperfusion diseases.
Citation of any reference in Section 2 of this application is not an admission that the reference is prior art.
The invention is based in part on the discovery of novel substituted tetracyclic benzamide derivatives and their demonstrated effects in the treatment of inflammation, cell death and in treating shock and reperfusion diseases.
Accordingly, in one aspect the invention includes a compound of Formula I, Formula Ia, Formula Ib, Formula II or Formula III, or a pharmaceutically acceptable salt or hydrate thereof (an xe2x80x9cIndeno[1,2-c]isoquinoline Compoundxe2x80x9d) as set forth below in the detailed description of the invention.
Also provided by the invention is a method for treating or preventing an inflammatory disease or a reperfusion diseasein a subject, comprising administering to a subject in need of such treatment or prevention an effective amount of an Indeno[1,2-c]isoquinoline Compound.
In a further aspect, the invention also includes a method for making an Indeno[1,2-c]isoquinoline Compound. 
The Indeno[1,2-c]isoquinoline Compounds can be used to treat or prevent a variety of conditions and diseases, including, but not limited to, an inflammatory disease or a reperfusion disease.
The invention also includes pharmaceutical compositions that comprise an effective amount of an Indono[1,2-c]isoquinoline Compound and a pharmaceutically acceptable carrier. The compositions are useful for treating or preventing an inflammatory disease or a reperfusion disease. The invention includes an Indeno[1,2-c]isoquinoline Compound when provided as a pharmaceutically acceptable prodrug, a hydrated salt, such as a pharmaceutically acceptable salt, or mixtures thereof.
The details of the invention are set forth in the accompanying description below. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, illustrative methods and materials are now described. Other features, objects, and advantages of the invention will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications cited in this specification are incorporated by reference.